ABSTRACT The prevalence of hypertension, which is predicted to be the leading global cause of death and disability by the year 2020, increases with age from 46% of U.S. adults aged 20-44 to >78% of U.S. adults above the age of 65. Less than half of elderly patients with hypertension achieve adequate blood pressure control and older hypertensive patients are significantly less likely to receive a thiazide prescription (first line anti-hypertensive) than younger patients. This suggests contemporary prescribing practices to the elderly are sub-optimal. Further, the development of antihypertensive drugs has been dramatically less productive than expected, making new mechanistic insights into age-dependent blood pressure regulation essential. This application will test the global hypothesis that attenuated mechanosensitive afferent renal nerve sympathoinhibitory reflexes evoke sodium chloride cotransporter-mediated renal sodium retention and age-dependent hypertension. These studies will employ our novel technique of selective afferent renal nerve ablation, a unique in-vivo surgical approach to activate the mechanosensitive afferent renal nerves, and genetic and pharmacological tools in 3, 8 and 16 month old Sprague-Dawley rats (model of normal aging) that exhibit age-dependent hypertension to provide new mechanistic insight into the pathophysiology of age-dependent hypertension. The following Specific Aims will be conducted to test this hypothesis: Specific Aim 1: Impairments in the renal sympathetic nerves contribute to age-dependent hypertension. Specific Aim 2: Attenuation of the mechanoreceptor- activated sympathoinhibitory afferent renal nerve natriuretic reno-renal reflex occurs in age-dependent hypertension. Specific Aim 3: Age-dependent elevations in sympathetic tone increase NCC activity, via a NE- ?1-adrenoceptor-gated WNK1-OxSR1 signal transduction pathway, to evoke renal nerve-dependent sodium retention and hypertension. These hypertension focused studies are central to the mission of the NIA, which is to understand the nature of the aging processes and diseases associated with aging to extend healthy years of life and the NHLBI, which is to promote the prevention and treatment of heart, lung and blood diseases. Specific Aim 1 will establish an age-dependent role of the renal sympathetic nerves in sodium excretion and blood pressure regulation during acute and chronic challenges to salt and water balance. Specific Aim 2 will establish a key role of an impairment in sensory renal mechanoreceptor activation that reduces central sympathoinhibitory signaling in the pathophysiology of age-dependent hypertension. Specific Aim 3 will establish the age-dependent actions of the sympathetic nervous system to regulate the sodium chloride cotransporter, via a novel ?1- adrenoceptor signal transduction pathway. Our innovative research strategy will define a novel age-dependent renal sympathetic nerve dependent mechanism through which sodium excretion and blood pressure is regulated, and will support U.S. prescribing guidelines and identify new therapeutic targets and treatment approaches for sympathetically mediated age-dependent hypertension.